The determinants of the relationship between the dose of furosemide and its effect have been insufficiently investigated. There are a number of predictable modulating mechanisms of this relationship. I propose systematic evaluation of a number of settings in humans in which these different mechanisms may be operative. By so doing, I hope to more fully understand the physiology of sodium reabsorption in a number of diseases, the pharmacology of furosemide, and perhaps most importantly, how to more rationally approach using furosemide in a wide variety of clinical settings. In brief, I propose studying the pharmacokinetic, pharmacodynamic aspects of furosemide in the following settings: 1) Settings with potentially decreased delivery of furosemide to its site of action. a) Patients with renal failure of various degrees of severity. b) Normal volunteers coadministered organic acids which potentially could decrease active transport of furosemide into the tubular lumen. 1. Probenecid; 2. Indomethacin. 2) Settings with potentially decreased delivery of sodium to the loop of Henle and with hemodynamic changes. a) Patients with congestive heart failure. b) Patients with hepatic disease. 3) Settings assessing the role of prostaglandins in mediating the effects of furosemide. a) Normal volunteers administered probenecid, and b) indomethacin.